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Biomedical subjects

K Nicolaou

Publications and source records attributed to K Nicolaou.

4 recordsLinked to original sources
PubMed2000

Combinatorial synthesis of novel and potent inhibitors of NADH:ubiquinone oxidoreductase.

BACKGROUND: NADH:ubiquinone oxidoreductase (complex I) is the first of three large enzyme complexes located in the cell's inner mitochondrial membrane which form the electron transport chain that carries electrons from NADH to molecular oxygen during oxidative phosphorylation. There is significant interest in developing small molecule inhibitors of this enzyme for use as biological probes, insecticides and potential chemopreventive/chemotherapeutic agents. Herein we describe the application of novel natural product-like libraries to the discovery of a family of potent benzopyran-based inhibitors. RESULTS: Initially a combinatorial library of benzopyrans, modeled after natural products, was synthesized using a solid phase cycloloading strategy. Screening of this diversity oriented library for inhibitory potency against NADH:ubiquinone oxidoreductase activity in vitro using bovine heart electron transport particles provided several lead compounds which were further refined through a series of focused libraries. CONCLUSIONS: Using this combinatorial library approach, a family of potent 2,2-dimethylbenzopyran-based inhibitors was developed with IC(50) values in the range of 18-55 nM. Cell-based assays revealed that these inhibitors were rather non-cytotoxic in the MCF-7 cell line; however, they were quite cytostatic in a panel of cancer cell lines suggesting their potential as chemotherapeutic/chemopreventive candidates.

Animals↗
PubMed1997

The chemical end-ligation of homopyrimidine oligodeoxyribonucleotides within a DNA triple helix.

BACKGROUND: Triple-helical nucleic acids, first reported in the late 1950s, are receiving attention for their possible involvement in controlling gene expression. Certain sequences of DNA are believed to form local triple-helical structures (H-form DNA), although this has not been directly observed in vivo. Studies carried out in our laboratories have suggested that self-replicating oligonucleotides could have been involved in chemical evolution via triple-helical intermediates. In addition to self-replication mechanisms, elucidating processes for the nonenzymatic elongation of biologically relevant polymers remains an important challenge in understanding the origin of life. To this end, we have studied a novel ligation of oligodeoxyribonucleotides that lie within a triple helix. RESULTS: The chemical end-ligation of homopyrimidine oligodeoxyribonucleotides on a triple helix is reported. This selective process, induced by cyanoimidazole, is facilitated by a template effect of the DNA aggregate and occurs between the 3' end (hydroxyl) of the third minor-groove-bound strand and the 5' end (phosphate) of the antiparallel oligopyrimidine strand. CONCLUSIONS: Double-helical homopurine/homopyrimidine DNA can serve as a template for the elongation of oligonucleotides in a manner that has not been described previously. The end-ligation of homopyrimidine oligomers, a nonenzymatic process, proceeds via a requisite triple-helical intermediate and constitutes an efficient and selective method for the template-directed elongation of nucleic acids. Such a process could conceivably have been involved in the elongation of primordial information-bearing biopolymers.

DNA↗
PubMed1996

Fluorescent taxoids.

BACKGROUND: Taxol is a natural product produced by the Pacific Yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. Taxol's biochemical mode of action has been well studied: it binds to microtubules, stabilizing them and preventing their depolymerization to tubulin subunits. At lower dosage levels, taxol also interferes with the normal dynamics of the tubulin-microtubule equilibrium. This biochemical effect causes taxol's ultimate physiological effect, cell cycle arrest; taxol is thought to block anaphase A of mitosis. Taxol also causes a number of intriguing secondary effects on interphase cells that are poorly understood. We believed that a bio-active fluorescent taxol derivative could be a useful tool in the study of these cellular mechanisms, especially in interphase cells. RESULTS: We have synthesized and characterized a series of stable, fluorescently labeled derivatives of taxol that bind to microtubules and have cytotoxicities similar to that of taxol. Fluorescence microscopy experiments in interphase human foreskin fibroblast (HFF) cells indicate that one of these, a sulforhodamine taxoid, is particularly well suited for optical microscopy. The use of this taxoid in HFF cells revealed a previously undetected localization of taxoids to the nucleolus during interphase. CONCLUSIONS: The production of a new fluorescent derivative of taxol provides a useful tool, enabling cellular biologists to study taxol's mechanism of action. It is hoped that this material will prove particularly useful for the study of taxol's effects upon interphase cells. Although in common usage for the last 20 years, Taxol is now a registered trademark of Bristol-Myers Squibb. The copyright of Bristol-Myers Squibb is recognized when Taxol or taxol is used in this article.

Antineoplastic Agents↗